All aerobic organisms continuously generate reactive oxygen species (ROS) such as superoxide anion and H2O2 as natural products of metabolism. ROS are potentially damaging to biomolecules, but can also be exploited by cells as weapons for attacking pathogens and as molecules for signaling. To balance the beneficial and potentially harmful effects of ROS, aerobic organisms are armed with a suite of anti-oxidant enzymes, and in eukaryotes, the only enzyme for superoxide is the superoxide dismutase (SOD). SODs use a metal co-factor such as Cu to catalyze at extraordinary rates, the disproportination of superoxide to O2 and H2O2. Until recently, the bimetallic Cu/Zn SOD was believed to be the only Cu SOD for eukaryotes, but in 2014, our lab discovered a new class of SODs that cannot bind Zn and lack sequences to cover the active site, hence, a Cu-only SOD with a highly unusual solvent exposed Cu co-factor. Cu-only SODs are wide-spread throughout the fungal kingdom as the sole extracellular SOD for fungi. In animals, the Cu-only SOD gene underwent twice duplication, resulting in 4x tandem repeats of Cu-only SODs on a single polypeptide we call CSRP (Cu-only SOD repeat protein). What sets the Cu-only SOD family apart from other SODs is their restricted localization and unusual open active site. All Cu-only SODs and CSRP molecules are predicted to be extracellular and remarkably, we find that Cu-only SODs do not acquire their Cu-cofactor from intracellular metal pools, unlike other eukaryotic secreted cuproproteins. Instead, Cu-only SODs are activated outside the cell by extracellular Cu. We hypothesize this new family of cuproproteins evolved to function exclusively outside the cell in extracellular redox biology. Here we combine biophysical, structural biology, and cell biology approaches to examine how the Cu site of Cu-only SODs is fine-tuned to capture Cu and not other metals outside the cell, and how the enzyme functions with extracellular superoxide. In eukaryotes, the primary source of extracellular superoxide is the NADPH oxidase (NOX), typically activated by Rho GTPases to produce ROS for signaling. Recently, we uncovered a surprising NOX - Cu-only SOD partnership in a unicellular fungal pathogen that represents a remarkably simple and unique form of Rho GTPase control of ROS. We will elucidate the mechanism underlying this redumentary system for ROS signaling and define how pathogenic yeasts can use Cu-only SODs and ROS to signal polarized growth. CSRP may likewise function in pathways involving NOX and ROS signaling. Using a vertebrate model, we find CSRP most abundantly expressed in tissues with a high capacity for regeneration by signaling through ROS. Our goals are to uncover the biochemical activities of CSRP and elucidate its function in possible relationship to NOX in tissues with high regenerative capacity. It is remarkable that nature has designed two distinct variations of Cu-containing SODs: the Cu/Zn versus the Cu-only. Our studies promise to uncover how the Cu-only SODs are specialized to operate outside the cell in redox and/or metallobiology.